Implants are used in medicine, which are introduced permanently or at least for an extended period into an animal body and/or a human body to fulfill replacement functions. Numerous implants and systems may be considered for this purpose, such as biosensors, dialysis tubing, drug delivery systems, pacemakers, cardiac implants, implants for joint replacement, vascular prostheses or stents.
Implants are typically identified by the organism as being foreign after they are introduced in the body. In response to the artificial surfaces, proteins aggregate thereon only a short time after implantation due to non-specific protein adsorption. These adsorbed proteins at least partially lose the three-dimensional structures thereof and serve as anchoring substrates for the aggregation of cells. These proteins are recognized by cells (including by thrombocytes, if the implant is introduced into the blood stream). This triggers non-defined cell coverage and/or an extracellular matrix of protein fibers (such as collagen) on the surface of the implant. This process is generally referred to as a foreign body reaction or fouling. Quite frequently, even collagen-containing encapsulation of the implant can be observed.
Implants encapsulated in tissue may lose the function thereof (for example, an analyte is able to reach the biosensor only partially, with time delay, or not at all, pores of a polymer membrane of the biosensor become clogged, or a stimulus threshold for stimulating implants changes). Moreover, encapsulated implants are more difficult to explant (for example, defective stimulation electrodes are not explanted, but remain in the body). In the human body, the described protein adsorption furthermore acts as an initiator for a foreign body reaction and may ultimately also lead to the formation of encapsulations and thrombi, which can be life-threatening for the patient.
However, this is not the only severe risk for the patient. Despite extensive progress in surgical medicine, infections following the introduction of a sterilized implant still represent very frequent complications. The adhesion of microorganisms (adhesion phase) always marks the beginning of an implant infection following implantation. The surface morphology and the physicochemical properties of the implant material are relevant for the adhesion of organisms to the implant surfaces. Binding is favored if biopolymers (in particular polysaccharides) have already adhered to the surface. Reproduction of the microorganisms results in extensive, and later explosive, three-dimensional colonization of the surface. The simultaneous bacterial synthesis of epoxy polysaccharides and other organic molecules causes the bacteria to be sheathed by a mucus-like matrix, which is referred to as a biofilm. If the biofilm is formed across a large area, the body's own antibacterial mechanisms as well as antibiotics are no longer able to prevent the organisms from spreading further on the implant and throughout the entire body. At times, this may result in life-threatening situations. An infection manifests itself to the patient by necrosis, chronic inflammations, abscesses, endocarditis, myocarditis, sepsis and the like. As many as one in five patients suffering from such infection dies within one year of becoming infected.
The bacteria causing the infection are usually introduced during implantation/revision surgery and cause either acute or latent infections. Staphylococci are responsible for these infections in 60 to 80% of cases (S. epidermis and S. aureus), but other bacteria such as E. coli also play a role. If typical antibiotic-(multi)resistant nosocomial microbes are introduced into the body, the situation can become particularly critical. If an infection involving biofilms occurs, it is frequently necessary to replace the implant with a new implant (referred to as revision surgery), since an antibiotics therapy alone is generally not sufficient. From the point of view of health care costs, infections pose a major problem; the administration of antibiotics alone may result in costs of approximately 5000 euros in certain situations, to which the costs for the new implant and the implantation are added. Infections of the pacemaker pocket and/or of an electrode system can occur with an incidence rate of up to 12%, for example. Often times a single implant replacement does not suffice since biofilms represent a focus of continuously recurring infections.
If a combination of an encapsulation of the implant and a bacterial infection occurs, the patient's immune system is substantially defenseless since immune cells are not able to penetrate to the bacterial center. This is particularly critical when replacing the implant (for example, when the service life of the implant is exhausted). During these replacements, the implant is typically introduced into the capsule formed by the previous implant. In general, this automatically also results in bacteria being introduced into the body and the collagen capsule. An infection of what is known as the pacemaker pocket generally forms just the starting point. The infection can then spread along the electrodes that are anchored in the heart. Medical procedures to disrupt or even remove the collagen-containing capsule are complex and presumably associated with a longer healing process.
In particular in view of an aging and multimorbid population, the complications that occur are particularly critical, and more implant replacements are needed at the same lifetime of the implants given patients' higher life expectancy. Multimorbidities, which is to say the simultaneous occurrence of multiple chronic diseases in a patient, pose additional risks. The risk of infection of patients with pacemakers/defibrillators/CRT devices is increased, for example, if they suffer from diabetes and renal insufficiency.
It is therefore of great importance to improve the compatibility of implants and substantially minimize a defense reaction of the patient's body against the implant. An improvement in the compatibility of visual prostheses, such as contact lenses, that can be attached externally to the body is known to be achievable by way of a coating, applied by way of plasma polymerization (Evaluation of plasma polymer-coated contact lenses by electrochemical impedance spectroscopy. Weikart C M, Matsuzawa Y, Winterton L, Yasuda H K. J Biomed Mater Res. 2001 Mar. 15; 54(4):597-607.). The coating protocols established for this purpose, however, are only successful on smooth surfaces. On these, however, the adhesion of the coating, such as under mechanical load, is often not sufficient. Such coatings are consequently not suitable for implants that are introduced into the body, especially for long-term use. Moreover, a plurality of implant surfaces do not have smooth surfaces, whereby the above-described coating protocols cannot be readily employed.
In addition, a number of surface modifications of the implant surface are known, which are intended to prevent colonization with bacteria (Implant infections: a haven for opportunistic bacteria. Schierholz J M, Beuth J., J Hosp Infect. 2001 October; 49(2):87-93. Review.). It is primarily antibiotically active molecules that bind to the surface. This is possible covalently by way of spacers; alternatively, the substances can be introduced in a matrix. The antibiotics can moreover be physically adsorbed on the surface or—mediated via charged molecules (such as tridodecylmethylammoniumchloride)—bind ionically to the surface. The incremental delivery of these molecules to the surrounding area may be expedient (TYRX™ antibacterial envelope from MEDTRONIC). The use of silver salts, silver ions, and metallic silver is also under discussion.
Additionally, it is known that polymers can be used as surface coatings which replicate the body's own antibiotically acting substances (End-Functionalized ROMP Polymers for Biomedical Applications. Madkour A E, Koch A H, Lienkamp K, Tew G N., Macromolecules. 2010 May 25; 43(10):4557-4561.). Approaches have also been described that are intended to prevent (proteins and) bacteria from adhering by modifying the hydrophobic surface properties, for example by binding hydrophilic chains and polymers (Staphylococcus aureus adhesion to titanium oxide surfaces coated with non-functionalized and peptide-functionalized poly(l-lysine)-grafted-poly(ethylene glycol) copolymers, OHarris L G, Tosatti S, Wieland M, Textor M, Richards R G., Biomaterials. 2004 August; 25(18):4135-48.). This paper also discusses the attempt to combine antibacterial and antiadhesive properties in vitro by using a coating made of polylysine (antibacterial) and polyethylene glycol (preventing the adhesion of biomolecules).
In many of these approaches it is unknown whether these are able to suppress the adhesion of microbes in a long-term stable manner—naturally, degrading processes in the body, which corrode the implant immediately after it has been introduced into the body, decisively influence the surface modification. The surface modification may thus lose the antibiotic action thereof very quickly, as a result of which a biofilm may form on the surface at an explosive rate.
If, additionally, the antibacterially acting substances intervene in the metabolism of the bacteria, minor genetic changes may render the antibiotically acting substances ineffective. The best example is multiresistant bacteria, against which no commercially available antibiotics are effective any longer. Approaches must be found that universally suppress the formation of biofilms, even in multiresistant strains. If antibiotically acting (“drug-eluting”) substances are delivered, it is at times possible to cover only short time periods due to the limited amount of the active ingredient.